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The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period ( n  = 5642 blood specimens, n  = 3814 children ages 1–59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P  = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger. In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al . here report a reduction of Campylobacter infection, supporting one mechanism for the intervention’s impact on mortality.

Giardia lamblia, the cause of giardiasis, significantly impacts patients with metabolic disorders related to insulin resistance (IR). Both giardiasis and metabolic disorders share elements such as chronic inflammation and intestinal dysbiosis, which substantially affect the metabolic and cytokine profiles of patients. This review discusses the mechanisms of virulence of G. lamblia, its influence on the immune system, and its association with metabolic disorders. The review aims to show how G. lamblia invasion acts on the immune system and the glucose and lipid metabolism. Key findings reveal that G. lamblia infection, by disrupting intestinal permeability, alters microbiota composition and immune responses, potentially impairing metabolic status. Future research should focus on elucidating the specific mechanisms by which G. lamblia influences the metabolism, exploring the long-term consequences of chronic infection, and developing targeted therapeutic strategies that include both parasitic and metabolic aspects. These insights underscore the need for a multidisciplinary approach to the treatment of giardiasis in patients with metabolic disorders.

IL-17A plays a crucial role in the immune defense against Giardia infection, yet its cellular sources remain incompletely defined. In this study, the site-specific expression and cellular origin of IL-17A were investigated, focusing on both adaptive and innate immune cells in the small intestine, Peyer’s patches and mesenteric lymph nodes of Giardia muris infected C57BL/6 mice. RT-qPCR analyses showed that IL-17A mRNA expression was significantly upregulated in the small intestine, slightly elevated in the Peyer’s patches and unchanged in the mesenteric lymph nodes. Flow cytometry revealed that CD4⁺ T helper cells in the lamina propria of the small intestine are the predominant source of anti-giardial IL-17A. No increase in IL-17A was detected by γδT cells, Tc cells, NK(T) cells, B cells, neutrophils, dendritic cells and innate lymphoid cells. Within the CD3 − innate cell population, increased IL-17A production was observed in MHC-II + CD11c + CD11b +/− cells, including a subset of cells expressing typical macrophage markers, namely MHC-II⁺CD11c⁺CD11b⁺CD64⁺F4/80⁺ cells. In T cell-deficient mice, both IL-17A expression and parasite clearance were severely impaired. Our findings demonstrate the importance of the adaptive immunity and simultaneously identify Th cells in the lamina propria as the main source of anti-giardial IL-17A, with a possible supporting role from macrophage-like antigen-presenting cells.

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

Giardia lamblia infections are nearly universal among children in low-income countries and are syndemic with the triumvirate of malnutrition, diarrhea, and developmental growth delays. Amidst the morass of early childhood enteropathogen exposures in these populations, G. lamblia–specific associations with persistent diarrhea, cognitive deficits, stunting, and nutrient deficiencies have demonstrated conflicting results, placing endemic pediatric giardiasis in a state of equipoise. Many infections in endemic settings appear to be asymptomatic/ subclinical, further contributing to uncertainty regarding a causal link between G. lamblia infection and developmental delay. We used G. lamblia H3 cyst infection in a weaned mouse model of malnutrition to demonstrate that persistent giardiasis leads to epithelial cell apoptosis and crypt hyperplasia. Infection was associated with a Th2-biased inflammatory response and impaired growth. Malnutrition accentuated the severity of these growth decrements. Faltering malnourished mice exhibited impaired compensatory responses following infection and demonstrated an absence of crypt hyperplasia and subsequently blunted villus architecture. Concomitantly, severe malnutrition prevented increases in B220+ cells in the lamina propria as well as mucosal Il4 and Il5 mRNA in response to infection. These findings add insight into the potential role of G. lamblia as a \"stunting\" pathogen and suggest that, similarly, malnourished children may be at increased risk of G. lamblia– potentiated growth decrements.

Giardiasis is a serious public health issue caused by Giardia lamblia . The medications used in its treatment induce unfavorable adverse effects. Furthermore, treatment failure and drug resistance are other challenges in its management. Vonoprazan is a safe, recently approved potassium-competitive acid blocker. The current study aimed to assess the potential therapeutic effects of vonoprazan, alone or in combination with metronidazole, on giardiasis. The efficiency of the treatment was evaluated by parasitological, histopathological, immunohistochemical, scanning electron microscopic, and biochemical studies. According to the results, the combination treatment significantly reduced the number of cysts in the stool and trophozoites in the small intestinal wash and ameliorated the intestinal pathological alterations. The expression of TNF-α and caspase-3 in the intestinal tissues was reduced. Also, there were reductions in the levels of IL-6, iNO, and MAD and an elevation in TAC levels in the serum. The combination therapy exhibited better efficacy than metronidazole alone. To sum up, this study underlines the suitability of using vonoprazan as an adjuvant to metronidazole in treating giardiasis.

ObjectivePsychological factors increase the risk to develop postinfectious IBS (PI-IBS), but the mechanisms involved are unclear. As stress affects the immune system, we investigated the potential interaction between psychological factors, the immune response against infectious gastroenteritis (IGE) and the development of IGE and PI-IBS in a large cohort exposed to contaminated drinking water.Design18 620 people exposed to contaminated drinking water (norovirus, Giardia lamblia, Campylobacter jejuni) were invited to participate in a prospective controlled cohort study. They were asked to complete questionnaires assessing demographic, psychological and clinical data during the outbreak and 1 year later. At both time points, in-depth immune function (peripheral blood and rectal biopsies) was studied in a subgroup of subjects.Results1379 subjects completed the questionnaires during the outbreak, of which 271 developed IGE. Risk factors for IGE included younger age, pre-existing dyspepsia-like symptoms, anxiety and drinking contaminated tap water. Anxiety scores before the outbreak inversely correlated with interleukin-2-expressing CD4+ T cells (r=0.6, p=0.01, n=23). At follow-up, 34 of 172 (20%) IGE subjects developed IBS compared with 24/366 exposed participants (7%, p<0.0001, χ2 test). A Th2 cytokine phenotype at time of infection was associated with increased risk for PI-IBS 1 year later. Except for increased B cell numbers, no evidence for systemic or rectal mucosal immune activation in PI-IBS was demonstrated at follow-up.ConclusionsOur study shows that the increased risk of patients with psychological comorbidity to develop PI-IBS may partly result from an increased susceptibility to develop IGE, possibly resulting from a Th2-immune bias.Trial registration number(ClinicalTrials.gov NCT01497847).

Giardia duodenalis is a globally prevalent enteric parasite capable of establishing both acute and chronic infections. While infection dose is known to influence early infection dynamics, its effect on immune activation and chronicity remains poorly defined. In this study, we investigated how varying inoculum sizes affect infection kinetics and immune development in both immunocompetent (C57BL/6J) and T cell–deficient (TKO) mice. High infection doses induced earlier cyst shedding and accelerated interleukin-17A (IL-17A) responses, while lower infection doses resulted in delayed immune activation. Despite these early differences, cumulative cyst excretion and clearance kinetics eventually converged across dose groups. In TKO mice, infection was not controlled regardless of dose, yet parasite loads plateaued, suggesting host-intrinsic limits to expansion. Longitudinal follow-up in C57BL/6J mice revealed persistent low-level infection and sustained upregulation of IL-17A, mannose-binding lectin 2 (Mbl-2) and inducible nitric oxide synthase (NOS2) up to six months post-infection, despite low trophozoite counts. These findings confirm a central role for IL-17A in anti-giardial immunity and suggest that infection dose modulates the timing but not the outcome of immune control. Persistent IL-17A signaling during chronic infection may contribute to long-term host-pathogen interactions, with potential implications for intestinal health and secondary pathogen resistance.

Giardia duodenalis is one of the most commonly found intestinal parasites in mammalian hosts. Infections can generally be cleared by mounting an adequate protective immune response that is orchestrated through IL-17A. This study was aimed to investigate if and how the intestinal microbiome affects the protective Th17 response against Giardia by analysing and comparing the immune response following a G. muris and G. duodenalis infection in antibiotic treated and untreated mice. Depletion of the intestinal flora by antibiotic treatment had a severe effect on the infection dynamics of both Giardia species. Not only duration of infection was affected, but also the parasite burden increased significantly. Markers associated with a protective immune response, such as IL-17A and mannose binding lectin 2 were still significantly upregulated following infection in the antibiotic-treated mice, despite the lack of protection. On the other hand, the antibiotic treatment significantly decreased the level of IgA in the intestinal lumen by affecting its transporter and by reducing the number of IgA + B-cells at the Peyer’s patches. Furthermore, the depletion of the gut microbiota by antibiotics also significantly lowered the intestinal motility. The combination of these factors likely results in a decreased clearance of the parasite from the intestinal tract.

Giardia duodenalis is an intestinal protozoan parasite common in low- and middle-income countries. Infection is often subclinical, even when it is associated with other pathologies like growth stunting in children. Recent longitudinal cohort studies have found Giardia more frequently in patients with milder symptoms and have even suggested that Giardia reduces rotavirus symptom severity. One potential mechanism for limiting disease severity due to other enteropathogens is the promotion of anti-inflammatory responses that limit pathology. Our lab previously showed that Giardia reduces production of interleukin (IL)-12 by dendritic cells stimulated with Toll-like receptor agonists. In this study, we show that Giardia increases the production of the anti-inflammatory cytokine IL-10 by mouse peritoneal macrophages in response to bacterial lipopolysaccharide. This potentiation is specific to IL-10, as no changes were seen in the production of the proinflammatory cytokine tumor necrosis factor ɑ. Moreover, peritoneal macrophages from mice lacking macrophage galactose-binding lectin, a pathogen recognition receptor that has been previously shown to bind N-acetylgalactosamine, failed to increase IL-10 production after stimulation with Giardia and lipopolysaccharide. Giardia’s immunoregulation of the IL-10 response may help us understand the parasite’s role in reducing diarrheal severity.